SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment

Abstract

Most tumors initially respond to cytotoxic treatments, but acquired resistance often follows. The tumor microenvironment (TME) is a major barrier to clinical success by compromising therapeutic efficacy, and pathological relevance of multiple soluble factors released by a therapeutically remodeled TME remains largely unexplored. Here we show that the secreted frizzled-related protein 2 (SFRP2), a Wnt pathway modulator, is produced by human primary fibroblasts after genotoxic treatments. SFRP2 induction is remarkable in tumor stroma, with transcription mainly modulated by the nuclear factor-κB (NF-κB) complex, a property shared by several effectors of the DNA damage secretory program. Instead of directly altering canonical Wnt signaling, SFRP2 augments β-catenin activities initiated by WNT16B, another soluble factor from DNA-damaged stroma. WNT16B recognizes cancer cell surface receptors including frizzled (FZD) 3/4/6, a process enhanced by SFRP2, coordinated by the co-receptor LRP6 but subject to abrogation by DKK1. Importantly, we found WNT16B plays a central role in promoting advanced malignancies particularly acquired resistance by counteracting cell death, an effect that can be minimized by a neutralizing antibody co-administered with classical chemotherapy. Furthermore, DNA damage-triggered expression of WNT16B is systemic, imaged by significant induction among diverse solid organs and circulation in peripheral blood, thereby holding promise as not only a TME-derived anticancer target but also a novel biomarker for clinical evaluation of treatment efficacy. Overall, our study substantiates the biological complexity and pathological implication of a therapy-activated TME, and provides the proof of principle of co-targeting tumor and the TME to prevent acquired resistance, with the aim of improving intervention outcome in an era of precision medicine.

Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis

“…To clarify whether SFRP2 increases or decreases as tumors progress, we previously found that SFRP2 signal intensity increased as a function of tumor volume using SFRP2-targeted molecular imaging of a mouse tumor in vivo [33]. Other studies confirmed our observation showing that overexpression of SFRP2 increases angiogenesis and tumor growth in vitro and in vivo , [8,9,4,6,34,1,7,2,3]. Furthermore, antagonizing SFRP2 with a monoclonal antibody inhibits tumor growth in vivo [10], which establishes the preponderance of evidence that SFRP2 stimulates, rather than suppresses, tumor growth.…”

“…Overexpression of transfected SFRP2 in MCF7 breast adenocarcinoma cells increased their resistance to apoptotic signals in vitro [6]. Likewise, SFRP2 is a key factor in chemotherapy resistance of damaged tumor microenvironment [7]. …”

Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential

“…However, overexpression of sFRP2 has been reported in renal cancer [8], human angiosarcoma, and breast cancer [21, 22], which leads to angiogenesis stimulation by activation of the calcineurin/NFATc3 pathway. Furthermore, recently enhanced sFRP2 expression has been associated with promoting therapeutic resistance and metastatic potential within solid tumors by specifically altering the tumor microenvironment [23, 24]. …”

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

“…Recent data demonstrated that HGF is a critical TME determinant of resistance to BRAF inhibitors, setting the baseline for combinations of HGF-targeting monoclonal antibodies and RTK inhibitors that dampen the receptor c-Met activation [78,79]. Identification of the distinct role of stromaderived WNT16B in prostate cancer strongly supports translational studies in cancer therapy, as evidenced by the pilot preclinical trial integrating a monoclonal WNT16B antibody and routine chemotherapy to treat prostate tumors [73]. It is tempting to compare the efficacy of WNT16B-implicated pathway blockade and a wider suppression of the TME response to genotoxicity by inactivating the NF-κB complex.…”

“…Expression of the secreted frizzled-related protein 2 (SFRP2), a typical modulator of Wnt signaling, is increased in the stroma damaged by the chemotherapeutic cycles [56]. Beyond holding the potential to promote angiogenesis via the calcineurin/NFAT signaling in a noncanonical Wnt pathway [71,72], SFRP2 can interact directly with WNT16B to enhance its canonical activities, eventually generating a substantially strengthened malignant phenotype including remarkable drug resistance in prostate cancer [73]. Data from targeting angiopoietins (Ang1, Ang2, Ang4) which cause CAF accumulation and neoangiogenesis in the TME, and TEK (referring to Tie1/Tie2) receptors responsible for the maturation and plasticity of blood vessels, are recently reported [74,75].…”